ORIGINAL RESEARCH

Intradermal Tranexamic Acid

ABSTRACT
BACKGROUND: Despite being an effective
treatment for melasma, there have been limited
reports on the long-term efficacy of intradermal
tranexamic acid (TA) injection. OBJECTIVE: This
study sought to evaluate the 48-week efficacy of a
4mg/mL intradermal TA injection for the treatment
of melasma. METHODS: Five female patients with
melasma participated in the 48-week follow-up
Injection for the Treatment of
Melasma: A Pilot Study with 48-week
Follow-up
by SUPARUJ LUEANGARUN, MD, MSc; PUNYAPHAT SIRITHANABADEEKUL, MD;
PRAPALPITCH WONGWICHARN, MD; CHUTIMON NAMBOONLUE, MD;
SARUN PACHARAPAKORNPONG, MD, MD; PREMJIT JUNTONGJIN, MD;
and THERDPONG TEMPARK, MD
Drs. Lueangarun, Sirithanabadeekul, Wongwicharn, Namboonlue, Pacharapakornpong, and Juntongjin are with the Division
of Dermatology at the Chulabhorn International College of Medicine of Thammasat University in Pathumthani, Thailand. Dr.
Tempark is with the Department of Pediatrics, Faculty of Medicine at Chulalongkorn University in Bangkok, Thailand.
J Clin Aesthet Dermatol. 2020;13(8):36–39

after receiving 4-mg/mL intradermal TA injections
on the face every two weeks for seven sessions
and a sunscreen prescription. Assessments were
performed at baseline and Weeks 4, 8, 12, 16,
and 48 using the modified Melasma Area Severity
Index (mMASI) score, melanin index, and patient
satisfaction score. Safety and adverse effects were
also evaluated. RESULTS: The mean (standard
deviation) age of patients was 53.6 (8.14) years
and Fitzpatrick Skin Type IV (60%) and Fitzpatrick
Skin Type V (40%) were observed. The mean
(standard deviation) duration of melasma was
7.6 (2.51) years and 60 percent of participants
reported a family history of melasma. There was a
significant decrease in mMASI score and melanin
index at 16 weeks, without a statistically significant
improvement of mMASI score at 48 weeks. Melasma
recurrence was observed in 60 percent of the
participants, with higher mMASI scores recorded,
but the severity remained less than at baseline.
The patient satisfaction score was lower from
Week 16 to Week 48. Interestingly, a statistically
significant decrease in the melanin index was
observed up to Week 48, with no serious adverse
effects. CONCLUSION: The 4-mg/mL intradermal
TA injection yields significant efficacy at Week 16;
however, melasma recurrence occurred during the
48-week follow-up. In addition to tranexamic acid
injections, maintenance therapy and sun protection
should be considered for patients with melasma.
KEY WORDS: Melasma, melasma pathogenesis,
melasma treatment, tranexamic acid, intradermal
microinjection
M
Melasma is a common acquired pigmentary
disorder of facial hyperpigmentation, with
characteristic presentations that include
symmetrically distributed, hyperpigmented
macules and patches at frequently sun-exposed
areas of the skin, especially on the face.1 There
are several treatment modalities available for
melasma, such as whitening agents, chemical
peeling, laser and light therapy.2 However, these
treatments can yield adverse effects such as
mottled hypopigmentation, irritation, acneiform
eruptions, and rebound hyperpigmentation.3
Tranexamic acid (trans-4-
aminomethylcyclohexane-carboxylic acid; TA) is
a plasmin inhibitor, with the synthetic derivative
of amino acid lysine that works by reversibly
blocking lysine binding sites on plasminogen
molecules to inhibit the plasminogen activator
(PA) from converting plasminogen to plasmin.4
The main mechanism of the hypopigmentation
effects of TA is due to its antiplasmin activity, with
a structural similarity relative to tyrosine that
can inhibit tyrosinase competitively.5,6 Whereas,
plasmin transforms the vascular endothelial
growth factor (VEGF) into a diffusing form,
which demonstrates a crucial role of TA following
histological examination in the reduction of
erythema and vascularities as well as the number
of mast cells in the dermis.7,8
In clinical studies, localized intradermal
TA injection can be efficacious for melasma
treatment,9–12 with a significant decrease in
pigmentation,13 little systemic absorption, and
no systemic side effects. However, the efficacy
of intradermal TA injections in previous studies
have been evaluated for only a short period
of time, while recurrence after cessation of
treatment seems very common.3 This study aimed
to evaluate the efficacy and safety profile of
long-term 48-week follow-up of intradermal TA
injection for the treatment of melasma.
METHODS
This prospective clinical trial was conducted
at Benjakiti Park Hospital from May 2017 to
November 2018 and included five female patients,
aged 26 to 60 years, with bilateral symmetric
melasma. Exclusion criteria included oral
contraceptive pill use, pregnancy and lactation
within 12 months prior to the study, a history
of coagulation and thrombotic disorder, use
of anticoagulants, allergy to TA, treatment for
melasma within six months prior to the study, and
history of herpes simplex lesions on the face. This

FUNDING: No funding was provided for this study.

DISCLOSURES: The authors have no conflicts of interest relevant to the content of this article.
CORRESPONDENCE: Suparuj Lueangarun, MD. MSc; Email: saoraya180@gmail.com

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 ORIGINAL RESEARCH

study was approved by Thammasat University’s

ethical review board in accordance with the
Declaration of Helsinki. All patients signed a
written informed consent form.
Intervention. Patient demographic data,
including age, sex, disease duration, and family
history of melasma, and skin phenotype, were
recorded. Patients were asked to apply topical
anesthetic cream (EMLA®, 2.5% lidocaine and
2.5% prilocaine; Astra Pharmaceuticals, Wayne,
Pennsylvania) on the face for 45 minutes under
occlusion, then wash it off before treatment with
4-mg/mL intradermal TA injection. Treatment
sessions took place every two weeks for a total
of seven sessions. The 30-gauge needles were
injected intradermally into the melasma lesion
at a 1-cm intervals (about 0.05 mL/1 cm2),11
approximately 3mL on each cheek, with an ice
pack applied to relieve pain. TA (Transamin®;
Daiichi Sankyo Co., Ltd., Tokyo, Japan) was
prepared under sterile conditions and drawn in
a 100-U/mL insulin syringe, then diluted with
normal saline up to 1mL for the 4mg/mL of FIGURE 1. Changes in mMASI score of intradermal TA injection in all patients, with significant reductions at 12 and 16
concentrated TA.10 All patients were prescribed a weeks (*p<0.05)
broad-spectrum sunscreen with a sun protection
factor of 50 for the 48-week study period.
The follow-up period included assessments
at baseline and Weeks 4, 8, 12, 16, and 48
using the modified Melasma Area and Severity
Index (mMASI score)14 applied by two blinded
dermatologists. A Biometric camera (Antera
3D®, Miravex Ltd., Dublin, Ireland) was used to
assess the melanin index. Patient satisfaction and
adverse side effects were also evaluated at each FIGURE 2. Clinical response of Case 1 at baseline and Weeks 4, 8, 12, 16, and 48
follow-up visit.
Statistical analysis. All outcome Efficacy assessment. There was statistical points at baseline and Weeks 4, 8, 12, 16, and
measurements were reported as means and significance for mMASI scores of 24±1.36, 48, respectively. Intradermal TA injection yielded
standard deviations (SDs). The mMASI score and 2.82±1.11 (p=0.18), 2.46±1.36 (p=0.07), a statistically significant improvement at all
melanin index were analyzed using the Wilcoxon 2.22±1.42 (31.48% reduction, p= 0.04*), follow-up periods. All participants demonstrated
signed-rank test. A p-value of less than 0.05 was 2.16±1.02 (33.33% reduction p= 0.04*), and an improvement in the melanin index at Week 48
considered to indicate statistical significance. The 1.95±0.75 (p=0.07) points at baseline and Weeks when compared to baseline (Figures 3 and 4).
statistician was blinded to data in the study. 4, 8, 12*, 16*, and 48, respectively. Moreover, there was a decrease in the patient
Intradermal TA injection yielded a statistically satisfaction score, where 0 points=worse and
RESULTS significant improvement at Week 12 and Week 10 points=excellent, at Week 4 after the last
Demographic data. There were five female 4 after the last treatment. However, a decrease treatment (Week 16), particularly from 6.90±2.01
patients, with a mean (SD) age of 53.6 (8.14) in the mMASI score was observed at Week 48, points to 4.80±2.75 points at Week 48 (p=0.042).
years and Fitzpatrick Skin Types IV (60%), and V without statistical significance. Three patients Adverse effects. Local side effects, such
(40%). The mean (SD) duration of melasma was showed recurrence of melasma with an increase as erythema and swelling, were observed
7.6 (2.51) years and 60 percent of patients had in mMASI score, albeit to a lesser degree than at and disappeared within 1 to 2 hours after
a family history of melasma and prior treatment baseline (Figures 1 and 2). injection. Other local side effects, including
with topical medication. None of the patients The melanin index showed a statistical pain, irritation, and bruising were minimal, with
reported any underlying diseases. Precipitating significance for 0.73±0.03, 0.71±0.03 (p=0.04), patient tolerance until the completion of study.
factors included sunlight exposure (100%) and 0.70±0.03 (p=0.04), 0.68±0.04 (p=0.04), There were no significant systemic side effects,
pregnancy (20%). 0.68±0.04 (p=0.04), 0.58±0.04 (p=0.04) such as gastrointestinal discomfort, headache,

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 ORIGINAL RESEARCH
FIGURE 3. Changes in melanin index following treatment with intradermal TA injection in all patients, with significant
reduction at all time points (*p<0.05)
FIGURE 4. Clinical response (upper row) and melanin index photography (lower row) changes of Case 5 at baseline and
Weeks 4, 8, 12, 16, and 48
hypomenorrhea, or spotting menstruation.15
DISCUSSION
To the best of our knowledge, this is the first
study to evaluate the long-term 48-week efficacy
and safety of intradermal 4-mg/mL TA injections
performed every two weeks for seven sessions for
the treatment of melasma, using both subjective
(mMASI and patient satisfaction scores) and
objective (biometric camera) assessments. There
was a significant decrease in mMASI score at
Week 16 for 33.33 percent compared to baseline
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38
(p=0.04).
Recently, there have been several reports
on the efficacy and side effects of localized
intradermal TA injections the treatment of
melasma using different concentrations of TA,
including 4 mg/mL, 20 mg/mL, and 100 mg/
mL, with the frequency ranging from weekly to
monthly and the treatment duration from eight
to 12 weeks.10–12,19,20 In our study, we chose to
use 4-mg/mL intradermal TA injection referred
to by previous research.11 For safety reasons, the
average dose of intradermal TA injection in our
patients was only 22mg (range: 12–32 mg),
much less than the antifibrinolytic dose of TA.15
Thus, no significant systemic side effects related to
TA were noted.
Following a pilot study of 4-mg/mL
intradermal TA injection,11 a decrease of 42.74
percent in mMASI score was observed after 12
weeks of treatment. Moreover, the melanin
level significantly decreased at Week 16 for
6.85 percent relative to baseline (p=0.04). In
addition, Saki et al12 observed improvements of
5.6 percent and 6.44 percent at Week 8 and Month
3 of follow-up, respectively, in the melanin level
following treatment of melasma with 20-mg/mL
intradermal TA injections.
However, in our study, the mMASI score
showed no statistically significant improvement
at Week 48 in 39.81 percent relative to baseline
(p=0.07). Meanwhile, three (60%) patients
showed recurrence of melasma with an increase in
the mMASI score, albeit still remaining improved
compared to baseline. Patient satisfaction scores
also significantly decreased from Week 16 to Week
48.
Interestingly, there was a statistically
significant decrease in the melanin index up
until Week 48 (0.58±0.04; 20.55% relative to
baseline; p=0.04). The prolonged pigmentation
improvement from melanin index evaluation
could have resulted from the use of sunscreen and
better sun-protection behaviors.16–18
In prior reports, a significant improvement in
mMASI score was observed at Week 8 and Week
12 from baseline, corresponding to our study
reporting a significant mMASI score improvement
at Week 12 and Week 16.9–11,19 Meanwhile, a
significant improvement of melanin level at Week
4 has been previously demonstrated,12 similar
to our study, in which we observed a significant
melanin index improvement after four weeks of
treatment compared to baseline.
In addition, most studies evaluated the efficacy
of intradermal TA injection in melasma treatment
after 12, 20, and 24 weeks.10–12,19 Meanwhile, the
gradual recurrence of melasma following the
4-mg/mL intradermal injection was commonly
observed at Week 24, but remained less severe
than the initial hyperpigmentation.11 Pazyar et
al9 detected a melasma recurrence rate of 54.5
percent at Week 24, comparable to in our study,
which showed a recurrence rate of 60 percent at
Week 16. In particular, with our long-term 48-
week follow-up period, the recurrence of melasma
was 60 percent, but was less severe than the initial
 ORIGINAL RESEARCH
hyperpigmentation.
Despite many treatment modalities for
melasma, none have been demonstrated to be
consistently satisfactory. Thus, melasma treatment
becomes a challenge for dermatologists, as no
gold-standard exists and recurrence is common.1
After treatments with TA, including oral,
topical application, localized intradermal
injection, localized microneedling, and other
combined modalities, such as intense pulse light
or neodymium-doped yttrium aluminum garnet
(Nd:YAG) laser,21 the initial efficacy and recurrence
of melasma were commonly observed.
A study from Bala et al22 reported efficacy
of oral TA in Asian skin, even at a low dose
of 500mg daily over a short period of 8 to 12
weeks. The authors concluded oral TA could
be a safe and convenient therapeutic option
to administer with minimal, reversible, and
mild side effects. Nonetheless, patients should
be cautiously screened for contraindications
and thromboembolic risk factors prior to the
commencement of therapy. Additionally, multiple
studies have also demonstrated that melasma
tends to recur following the cessation of oral TA
treatment.23,24
For topical treatment, triple combination
(containing fluocinolone acetonide,
hydroquinone, and tretinoin) therapy also showed
relapse as early as 1 to 2 weeks after treatment
cessation.25 Even with maintenance treatment
with triple combination therapy, Arellano et
al18 reported relapse in 47 percent of patients
after six months, particularly among those with
severe melasma at baseline, with a median
relapse time of 190 days. Meanwhile, treatment
with a 1064-nm Q-switched Nd:YAG laser and
a 12-week follow up after the last laser session
noted partial recurrence of melasma in all cases.26
After treatment with copper bromide lasers, Lee
et al27 recorded recurrence of melasma after six
months in 30 percent of patients. Thus, the high
prevalence of melasma recurrence with previous
intradermal, oral TA, topical, and laser treatment
modalities were compatible with the findings
of the our 48-week follow-up study. Despite
melasma recurrence, our study found that the
mMASI score was still better than at baseline,
while the melanin index also showed a significant
improvement with patient satisfaction.
Considering this, localized intradermal TA
injection could be efficacious for melasma
treatment. Nonetheless, it could be recommended
as a combination treatment paired with other
modalities, such as topical and laser therapies, or
maintenance therapy to decrease the relapse rate
of melasma.
Limitations. Our study was limited by the
small number of patients and lack of a control
group.
CONCLUSION
Localized 4-mg/mL intradermal TA injection
yielded significant efficacy at Week 16 after
treatment, but a 60-percent recurrence rate of
melasma was observed at Week 48. However, the
mMASI score and melanin index were still better
than at baseline, with patient satisfaction and no
serious side effects. Hence, localized intradermal
TA injection might be a promising therapeutic
option as monotherapy or a combination
treatment for melasma due to its efficacy
and safety profile. However, the recurrence
of melasma is expected during the follow-up
period from 16 to 48 weeks. Thus, the inclusion
of maintenance therapy and sun protection are
strongly recommended to improve efficacy and
decrease the recurrence of melasma.
ACKNOWLEDGMENTS
The authors would like to extend special thanks
to Dr. Voraphol Vejjabhinanta for the initiation and
Ms. Sunattee Kessung for her assistance in editing
and revising this manuscript.
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